Carboplatin Induction Chemotherapy in Clinically Lymph Node–positive Bladder Cancer

Take Home Message No guideline recommendations exist for the treatment of cisplatin-ineligible patients with clinically lymph node–positive (cN+) bladder cancer. In this study, carboplatin-based induction chemotherapy appeared to be an attractive alternative before radical cystectomy for this population. In particular, patients with cN1 disease who are not eligible for cisplatin may benefit from gemcitabine/carboplatin induction chemotherapy.


Introduction
Bladder cancer (BCa) accounted for more than 80 000 new cancer cases in the USA in 2021 [1]. Among patients with muscle-invasive bladder cancer (MIBC), up to one-third present with clinically lymph node-positive (cN+) disease on modern staging; these patients have a worse prognosis than for those with clinically lymph node-negative disease [2][3][4][5][6][7]. The optimal treatment for cN+ disease has not been established, but most patients seem to benefit from systemic therapy followed by radical cystectomy (RC) in cases with a response to systemic therapy. This population has been excluded from neoadjuvant chemotherapy trials, but according to more modern imaging, some of the patients in the neoadjuvant chemotherapy clinical trials would be today considered as having cN+ status [8][9][10].
Currently, eligible patients with cN+ disease receive upfront cisplatin-based combination induction chemotherapy (IC), followed by RC in cases with a clinical response, with some evidence regarding the benefit of consolidative therapy [11][12][13][14]. Nevertheless, despite the benefit of cisplatin-based IC before RC in this setting, little evidence exists regarding the benefit of other IC regimens, specifically for cisplatin-ineligible patients. However, up to 50% of patients with non-organ-confined BCa may be ineligible for cisplatin-based chemotherapy because of renal impairment, hearing loss, other medical comorbidities, and/or poor performance status [15]. Current guidelines provide no conceptual framework for cisplatin-ineligible patients with cN+ disease that is potentially curable.
By analogy to metastatic BCa, for which carboplatin is recommended for cisplatin-ineligible patients and achieves response rates up to 44% [16,17], gemcitabine/carboplatin IC is often considered for patients with cN+ disease. The aim of this study was to compare the oncological efficacy of gemcitabine/carboplatin IC versus cisplatin-based combination IC in patients with cN+ BCa. Both groups underwent RC as consolidative therapy. Pathological and survival endpoints were compared between the groups.

Study population
This is a retrospective fixed cohort study. We retrospectively reviewed

Propensity score matching
We used propensity score matching (PSM) to adjust for different sample sizes and to balance the characteristics of different treatment groups. We

Statistical analysis
Results are reported as the frequency and proportion for categorical variables and as the mean and standard deviation (SD) for continuous variables. Data for continuous variables were tested for a normal distribution using the Shapiro-Wilk test. If normally distributed, continuous variables were compared using a two-sample independent t test.
Continuous variables with a non-normal distribution were compared using the Wilcoxon rank-sum test. All categorical variables were compared using a v 2 test or Fisher's exact test, as appropriate.
We used logistic regression modeling to test the association of the chemotherapy regimen administered with pCR, pOR, pNR, and ypN status at RC. Survival differences between groups were evaluated using the Kaplan-Meier method and significance across groups was tested with the log-rank test. Multivariable Cox proportional-hazards models were applied to assess the association of clinicopathological features with OS and CSS in the overall cohort as well as in cN subgroups.
Statistical analysis was performed using R v4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). All tests were two-sided, and p values <0.05 were considered statistically significant.

Baseline characteristics
In total, 369 patients fulfilled the inclusion criteria, of whom 315 received cisplatin-based IC and 54 gemcitabine/carboplatin (Supplementary Table 1 Fig. 1A). Figure 1B shows Kaplan-Meier CSS curves for patients with pOR; there was no significant difference in survival between the IC regimens.
For the cN1 subgroup, there was no significant difference in OS (p = 0.77) or CSS (p = 0.7; Fig. 2A) between the IC regimens, but there was a difference in CSS in favor of cisplatin in the cN2/3 subgroup (p < 0.001; Fig. 2B). In the ypN0 subgroup, there was no significant difference in CSS (p = 0.5; Fig. 2C) or OS (p = 0.07) between the IC regimens.

Discussion
Oncological outcomes of cisplatin-based chemotherapy are considered superior to those with gemcitabine/carboplatin for cisplatin-eligible patients with BCa. In our study, the pOR rate was 27% for platinum-based IC among patients with cN+ BCa, and the pOR rate with cisplatin-based combination IC was 7% better than with gemcitabine/carboplatin, although the difference was not statistically significant (p = 0.4). Cisplatin-based combination IC conferred significant OS and CSS benefits in comparison to gemcitabine/carboplatin IC, driven mainly by the benefit for patients with cN2-N3 disease. These results align with previous small phase 2 studies that showed favorable response rates [19] and median disease-related survival [20] for cisplatinbased chemotherapy in comparison to carboplatin-based regimens. However, the only phase 3 head-to-head comparison of cisplatin-based versus carboplatin-based combination chemotherapy in cisplatin-eligible patients did not find a significant difference in median OS [21]. Moreover, on the basis of randomized controlled trials in the immunotherapy era (DANUBE, IMvigor130, KEYNOTE-361), it was suggested that carboplatin treatment in metastatic BCa may be more effective than previously thought. A recent network meta-analysis of these trials demonstrated that cisplatin-and carboplatin-based chemotherapy had similar efficacy in terms of OS and pCR rates [22].
In the cN1 subgroup, there was no significant difference in OS, CSS, or pOR between the cisplatin and  gemcitabine/carboplatin IC groups. Of the cN1 subgroup, 24% experienced a pOR, highlighting the real benefit of IC followed by RC in patients with limited nodal involvement. This may reflect the more beneficial nature of IC in cN1 in comparison to cN2-3 stages [12]. Furthermore, patients with cN1 disease are more likely to have false-positive imaging in comparison to patients with cN2/3 disease [11]. However, patients with cN+ status that remain ypNpositive after RC have significantly worse survival outcomes, regardless of cN stage [12,13,23]. Moreover, a multi-institutional analysis of 304 patients with cN+ BCa treated with IC and RC did not find a significant difference in OS between cN1 and cN2-3 cases [13]. In addition, more than 45% of the patients with cN1 stage in our study remained ypN-positive at final pathology. These findings support the overall value of IC and the potential benefit of gemcitabine/carboplatin in patients with cN1 BCa who are ineligible for cisplatin.
Several factors support the use of carboplatin-based combination chemotherapy in cisplatin-ineligible patients with cN+ BCa instead of surgery alone. While approximately 25% of patients with ypN-positive disease can be cured with RC and extended PLND alone [24], a population-based study showed that 5-yr OS in cN+ BCa was 31% for patients treated with preoperative chemotherapy followed by RC versus 19% for patients who underwent RC alone [14]. For cisplatin-ineligible patients with advanced urothelial cancer, depending on the regimen (methotrexate/carboplatin/ vinblastine vs gemcitabine/carboplatin), carboplatin induced overall response rates that ranged between 30.3% and 41.2% [16]. However, the sequence for carboplatin administration may be important. A retrospective study recently showed that ypN-positive patients at RC did not benefit from carboplatin-based adjuvant chemotherapy when compared to RC alone [25]. Of note, none of these patients had received preoperative chemotherapy and the study did not provide data on clinical node stage [25]. In summary, chemotherapy or RC alone are generally insufficient to cure metastatic BCa regardless of the regimen, suggesting an overall benefit from a multimodal treatment approach in the cN+ setting, even in cisplatin-ineligible patients [14,[26][27][28].
We acknowledge that our study has several limitations. First, owing to the retrospective design, the small sample size, and the limited number of events in the carboplatin group, the study may have been underpowered for detection of a difference between the two treatment groups. In addition, despite no significant differences in baseline variables between the groups after PSM, our cohort may be subject to an inherent selection bias. Nonetheless, the data provide evidence for further prospective hypothesis testing. Second, data on renal function and on cisplatin ineligibility would be helpful for better stratification of patients in addition to the quality criteria applied and better correction for cofounders during statistical analyses. Moreover, we do not know whether cisplatin-eligible patients received gemcitabine/carboplatin and we do not report on further cisplatin ineligibility criteria, including performance scores, regimen switches, the treatment dose, or IC-induced toxicities. Third, we do not provide data on restaging after IC to assess the clinical response to IC and did not include patients who experienced progression on IC and therefore did not undergo RC. This may pose a bias towards patients with a better response to IC and a lower progression rate in one of the treatment groups. In general, RC was only performed if there was no obvious progression during IC. Fourth, we acknowledge the limitations concerning the accuracy of clinical staging and the benefits of modern staging technologies [10]. Nonetheless, more than 50% of the patients remained ypN-positive at RC, indicating correct clinical prediction of lymph node metastasis in these cases. Moreover, RC with PLND is the gold standard for lymph node staging. Fifth, the multicenter design means that multiple surgeons were involved and there was no standardized IC schedule or standardized staging or assessment of pathological specimens, and several cisplatin-based regimens were considered. We tried to mitigate these shortcomings by applying PSM. In summary, if patients respond to IC, gemcitabine/carboplatin results in similar survival outcomes to those with cisplatin-based regimens. Furthermore, there was no survival difference among cN1 patients when stratified by IC regimen. Thus, carboplatin should be a treatment option for selected cisplatin-ineligible patients with BCa who may benefit from intensification of gemcitabine/carboplatin with novel therapies or novel targeted therapies combining immune therapies and possibly enfortumab vedotin (eg, NCT05239624) [29,30].

Conclusions
Cisplatin-based IC seems to be superior to gemcitabine/ carboplatin and should be the standard for patients with cisplatin-eligible cN+ BCa. Nevertheless, carboplatin-based IC treatment appears to be an attractive alternative for patients with cisplatin-ineligible cN+ BCa before RC. In particular, selected cisplatin-ineligible patients with cN1 disease may benefit from gemcitabine/carboplatin IC. Patients who experienced a pathological response to IC had better survival regardless of the IC regimen. cN+ BCa is a heterogeneous disease that deserves better risk stratification to guide clinical decision-making.